Natural killer (NK) cells are a third subtype of lymphocytes besides B and T cells. NK cells provide an important immune function in the defense against viruses and other intracellular pathogens. Unlike B and T cells, NK cells do not exhibit specificity for antigen. They acquired their name because they can kill cells without prior stimulation by antigen. The killing of normal healthy cells is prevented by inhibitory receptors on NK cells that recognize major histocompatibility class I molecules. A large number of receptors, both activating and inhibitory, that regulate the cytotoxic response of NK cells have been described. In order to evaluate the contribution of individual receptors to the control of NK cell activation, mice defective in a given NK cell inhibitory receptor have been used. In addition, a search for the mouse receptor equivalent to the killer cell immunoglobulin-like receptors (KIR) on human NK cells was undertaken. The mouse inhibitory receptor gp49B is interesting because it is expressed on several cell types that can release granules during activation. Such cells include NK cells, mast cells, and neutrophils. An influx of eosinophils into airway spaces is characteristic of allergic asthma and may contribute to pathogenesis such as airway hyperresponsiveness and remodeling, as well as excessive mucus production. We have shown that infiltration of mouse lungs by eosinophils during allergic inflammation is under negative control by the inhibitory receptor gp49B. gp49B, an Ig-like receptor, is known to negatively regulate mast cells and neutrophils through immuno-receptor tyrosine-based inhibition motifs (ITIM) in its cytoplasmic tail. Using mice deficient in gp49B (gp49B KO), we observed an increase in allergic inflammation in the lungs of Ascaris suum-infected, ragweed (RW) sensitized mice upon RW challenge, as compared to C57BL/6 wild type controls. Expression of gp49B was detected on peripheral eosinophils of control mice and on eosinophils from lungs of animals sensitized and challenged with RW. Furthermore, an increase in conjunctival inflammation, with a predominance of eosinophils, neutrophils, and degranulated mast cells, was observed in RW-sensitized gp49B KO animals that had been challenged in the eye, as compared to C57BL/6 controls. These data provide evidence of a functional inhibitory receptor on eosinophils which has the important protective function of dampening eosinophil-mediated allergic inflammation. A property common to the immune system and the nervous system is regulation by a highly complex and adaptable network of cellular interactions. Major histocompatibility complex (MHC) class I molecules, which are ligands of antigen-specific receptors on CD8 T cells and of inhibitory receptors on NK cells, have an important and surprising role in the control of activity-dependent neuronal plasticity in the central nervous system (CNS). While expression of MHC class I molecules in neurons has been reported, corresponding immune receptors have not been identified in the central nervous system. We have shown that a killer cell imunoglobulin-like receptor (KIR) gene is selectively expressed in subregions of the mouse brain where synaptic plasticity and neurogenesis occur, including olfactory bulbs, rostral migratory stream, and dentate gyrus of hippocampus. These results suggest new functions for KIR in the CNS. Uterine tissue in early human pregnancy is characterized by extensive vascular remodeling, invasion of fetal trophoblast cells, and by an abundance of maternal natural killer (NK) cells. Trophoblast cells express membrane-bound and soluble isoforms of the non-classical major histocompatibility class I molecule HLA-G. How NK-trophoblast cell interactions influence vascular remodeling is unknown. We have shown that interferon-gamma secretion by resting NK cells is induced by soluble, but not solid-phase antibodies to the killer cell immunoglobulin-like receptor (KIR) 2DL4, a receptor for HLA-G. KIR2DL4 is constitutively internalized into Rab5-positive compartments by a dynamin-dependent process. Soluble HLA-G was endocytosed into KIR2DL4-containing compartments in NK cells and in 293T cells transfected with KIR2DL4, as shown by confocal microscopy. The profile of genes upregulated by KIR2DL4 engagement on resting NK cells suggests a role in vascularization. IL-8 secretion was induced by transfection of KIR2DL4 into 293T cells, and occurred only with recombinant forms of KIR2DL4 that trafficked to endosomes. We propose that soluble HLA-G produced by fetal trophoblast cells activates maternal NK cells through endocytosis of KIR2DL4, thereby promoting vascularization during implantation.